Shensong Yangxin (SSYX) ameliorates disordered excitation transmission by suppressing cardiac collagen hyperplasia in rabbits with chronic myocardial infarction

Abstract

The traditional Chinese medicine Shensong Yangxin (SSYX) can improve the clinical symptoms of arrhythmia in an integrated manner. This study aimed to investigate the electrophysiological effect of SSYX on the hearts of myocardial-infarcted rabbits and further explore the mechanism by which SSYX alleviates myocardial fibrosis. Myocardial infarction (MI) was established in rabbits by ligation of the left circumflex coronary. The rabbits were treated with SSYX (0.5 g/kg/d) or saline for 8 weeks by oral administration. Microelectrode array (MEA) technology was used in vivo for extracellular electrophysiological recordings of the infarct border zone. Masson’s trichrome staining was used to observe myocardial fibrosis. Western blotting was performed to evaluate the protein expression levels of collagen I (COL I) and collagen III (COL III). Quantitative real-time polymerase chain reaction (real-time PCR) was performed to evaluate the TGF-β1 and MMP-2 mRNA expression levels. The results showed that the total activation time (TAT) and the dispersion of TAT were significantly increased and the excitation propagation markedly disordered after MI. SSYX could significantly decrease TAT and the dispersion of TAT, and significantly ameliorate the chaotic spread pattern of excitation. Furthermore, SSYX treatment could significantly decrease COL I and COL III protein levels and down-regulate TGF-β1 and MMP-2 mRNA expression levels in MI rabbits. It was concluded that SSYX may ameliorate cardiac electrophysiological abnormalities in infarcted hearts by decreasing the protein levels of COL I and COL III, down-regulating the mRNA expression levels of TGF-β1 and MMP2, and thereby reducing adverse cardiac remodeling.

Keywords

Shensong Yangxin / myocardial infarction / excitation transmission / collagen / hyperplasia

References

[1] YuPJ, CassiereHA, KohnN, et al. . Myocardial infarction classification on outcomes in nonemergent coronary artery bypass grafting. Ann Thorac Surg, 2015, 100(5): 1588-1593 PMID: 26206722

[2] HayashiM, ShimizuW, AlbertC M. The spectrum of epidemiology underlying sudden cardiac death. Circ Res, 2015, 116(12): 1887-1906 PMID: 26044246

[3] BurchfieldJS, XieM, HillJA. Pathological ventricular remodeling: mechanisms: part 1 of 2. Circulation, 2013, 128(4): 388-400 PMID: 23877061 PMCID: 3801217

[4] RingenbergJ, DeoM, Filgueiras-RamaD, et al. . Effects of fibrosis morphology on reentrant ventricular tachycardia inducibility and simulation fidelity in patient-derived models. Clin Med Insights Cardiol, 2014, 8: 1-13 PMID: 25368538 PMCID: 4210189

[5] AndersonML, PetersonED, PengSA, et al. . Differences in the profile, treatment, and prognosis of patients with cardiogenic shock by myocardial infarction classification: A report from NCDR. Circ Cardiovasc Qual Outcomes, 2013, 6(6): 708-715 PMID: 24221834

[6] LuHR, RohrbacherJ, VlaminckxE, et al. . Predicting drug-induced slowing of conduction and pro-arrhythmia: identifying the 'bad' sodium current blockers. Br J Pharmacol, 2010, 160(1): 60-76 PMID: 20331615 PMCID: 2860207

[7] BorowiczKK, BanachM. Antiarrhythmic drugs and epilepsy. Pharmacol Rep, 2014, 66(4): 545-551 PMID: 24948053

[8] WuY. Construction of the vessel-collateral theory and its guidance for prevention and treatment of vasculopathy. Front Med, 2011, 5(2): 118-122 PMID: 21695614

[9] LiuM, ZhaoS, WangY, et al. . Identification of multiple constituents in Chinese medicinal prescription Shensong Yangxin capsule by ultra-fast liquid chromatography combined with quadrupole time-of-flight mass spectrometry. J Chromatogr Sci, 2015, 53(2): 240-252 PMID: 24872525

[10] LiuY, LiN, JiaZ, et al. . Chinese medicine Shensong Yangxin is effective for patients with bradycardia: results of a randomized, double-blind, placebo-controlled multicenter trial. Evid Based Complement Alternat Med, 2014, 2014(1): 605 714-605 714

[11] ZouJG, ZhangJ, JiaZH, et al. . Evaluation of the traditional Chinese Medicine Shensong Yangxin capsule on treating premature ventricular contractions: a randomized, double-blind, controlled multicenter trial. Chin Med J (Engl), 2011, 124(1): 76-83

[12] FujitaM, MorimotoY, IshiharaM, et al. . A new rabbit model of myocardial infarction without endotracheal intubation. J Surg Res, 2004, 116(1): 124-128 PMID: 14732358

[13] DheinS, ManiconeN, MullerA, et al. . A new synthetic antiarrhythmic peptide reduces dispersion of epicardial activation recovery interval and diminishes alterations of epicardial activation patterns induced by regional ischemia. A mapping study. Naunyn Schmiedebergs Arch Pharmacol, 1994, 350(2): 174-184 PMID: 7990974

[14] AminoM, YoshiokaK, TanabeT, et al. . Heavy ion radiation up-regulates Cx43 and ameliorates arrhythmogenic substrates in hearts after myocardial infarction. Cardiovasc Res, 2006, 72(3): 412-421 PMID: 17054928

[15] SmaillBH, ZhaoJ, TrewML. Three-dimensional impulse propagation in myocardium: arrhythmogenic mechanisms at the tissue level. Circ Res, 2013, 112(5): 834-848 PMID: 23449546

[16] NavarreteEG, LiangP, LanF, et al. . Screening drug-induced arrhythmia [corrected] using human induced pluripotent stem cell-derived cardiomyocytes and low-impedance microelectrode arrays. Circulation, 2013, 128: S3-S13 PMID: 24030418

[17] KandelSM, RothBJ. The mechanism of reflection type reentry: A simulation study. J Cardiovasc Electrophysiol, 2015, 26(12): 1370-1375 PMID: 26269355

[18] MihicA, CuiZ, WuJ, et al. . A Conductive polymer hydrogel supports cell electrical signaling and improves cardiac function after implantation into myocardial infarct. Circulation, 2015, 132(8): 772-784 PMID: 26304669

[19] MajumderR, NayakAR, PanditR. Nonequilibrium arrhythmic states and transitions in a mathematical model for diffuse fibrosis in human cardiac tissue. PLoS One, 2012, 7(10): e45040-e45040 PMID: 23071505 PMCID: 3466321

[20] TschabrunnCM, RoujolS, NezafatR, et al. . A swine model of infarct-related reentrant ventricular tachycardia: Electroanatomic, magnetic resonance, and histopathological characterization. Heart Rhythm, 2016, 13(1): 262-273 PMID: 26226214 PMCID: 4747106

[21] JenkinsG. The role of proteases in transforming growth factor-beta activation. Int J Biochem Cell Biol, 2008, 40: 1068-1078 PMID: 18243766

[22] ShenN, LiX, ZhouT, et al. . Shensong Yangxin capsule prevents diabetic myocardial fibrosis by inhibiting TGF-beta1/Smad signaling. J Ethnopharmacol, 2014, 157: 161-170 PMID: 25267579

[23] ShiT, YaoZ, QinZ, et al. . Identification of absorbed constituents and metabolites in rat plasma after oral administration of Shen-Song-Yang-Xin using ultra-performance liquid chromatography combined with quadrupole time-of-flight mass spectrometry. Biomed Chromatogr, 2015, 29(9): 1440-1452 PMID: 25708105